The primary long term objective of this proposal is to evaluate novel therapies for breast cancer that are based on, or integrated with, laboratory findings. This proposal is designed to combine and focus in a BREAST CANCER TREATMENT GROUP (BCTG) the extensive resources, experience and capabilities of several clinical and laboratory investigators within the Johns Hopkins Oncology Center. This group will focus on the development and testing of novel approaches designed to augment the efficacy of chemotherapy in the treatment of breast cancer. This will be accomplished because of a number of critical strengths which will be effectively coordinated by the proposal. These include, (1) a large clinical breast cancer research program which emphasizes the rapid implementation of innovative therapies for women with metastatic breast cancer, (2) investigators with a proven track record in the design and implementation of innovative therapeutic trials combining novel treatments with close laboratory correlations, (3) a breast cancer laboratory program which interacts closely with the clinical program and has expertise in areas of immediate clinical applicability such as programmed cell death and modulation of drug resistance, (4) a number of group members primarily active in associated laboratory and clinical programs such as New Drug Development and Pharmacology who bring critical expertise to the problems of breast cancer and (5) exceptional expertise in clinical trial design, statistics and data management. This proposal augments these strengths by defining an organizational structure of one Clinical and one Laboratory Program which will work closely together in the evaluation of three separate strategies to improve the therapy of metastatic breast cancer. These strategies focus on (1) Reversal of Drug Resistance by Inhibition of DNA Repair, (2) Optimal sequencing of the Taxol/Cyclophosphamide combination for metastatic breast cancer and, (3) Augmentation of Cytotoxicity by Modulation of protein kinase C. The formation of the BCTG will, (1) ensure close interaction between dedicated laboratory and clinical investigators at all stages of drug development, (2) facilitate optimal study design by input from both Clinical and Laboratory members of the Group at an early stage of protocol design and, (3) monitor and ensure strict adherence to RPA guidelines, accrual goals, protocol eligibility, quality control, study monitoring and data collection, management and analysis. Two protocols are submitted with this proposal which reflect the strengths of the application. These comprise a trial of the combination of taxol and cyclophosphamide in women with breast cancer with tissue biopsies to evaluate mechanisms of resistance and a study of novobiocin to reverse alkylating agent drug resistance in women with metastatic breast cancer undergoing high-dose chemotherapy.